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Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10–10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10–6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10–3; p = 2.29 × 10–3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10–3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.
For many us who have studied, researched, written, and taught about the influenza pandemic of 1918–19, the current period of the global viral pandemic is eerily and unpleasantly familiar. Today, the rapid global spread of a virus has prompted policies calling for widespread closures, social distancing, constant handwashing, and public mask wearing in additional to other non-pharmaceutical interventions (NPIs). We have also seen pushback and resistance to these directives as well as substantial mismanagement of resources and a flood of misinformation. Much health policy has been inconsistently set at the local rather than federal level. These responses to our current pandemic closely mirror those to the pandemic 102 years ago.
Disturbed sleep and activity are prominent features of bipolar disorder type I (BP-I). However, the relationship of sleep and activity characteristics to brain structure and behavior in euthymic BP-I patients and their non-BP-I relatives is unknown. Additionally, underlying genetic relationships between these traits have not been investigated.
Relationships between sleep and activity phenotypes, assessed using actigraphy, with structural neuroimaging (brain) and cognitive and temperament (behavior) phenotypes were investigated in 558 euthymic individuals from multi-generational pedigrees including at least one member with BP-I. Genetic correlations between actigraphy-brain and actigraphy-behavior associations were assessed, and bivariate linkage analysis was conducted for trait pairs with evidence of shared genetic influences.
More physical activity and longer awake time were significantly associated with increased brain volumes and cortical thickness, better performance on neurocognitive measures of long-term memory and executive function, and less extreme scores on measures of temperament (impulsivity, cyclothymia). These associations did not differ between BP-I patients and their non-BP-I relatives. For nine activity-brain or activity-behavior pairs there was evidence for shared genetic influence (genetic correlations); of these pairs, a suggestive bivariate quantitative trait locus on chromosome 7 for wake duration and verbal working memory was identified.
Our findings indicate that increased physical activity and more adequate sleep are associated with increased brain size, better cognitive function and more stable temperament in BP-I patients and their non-BP-I relatives. Additionally, we found evidence for pleiotropy of several actigraphy-behavior and actigraphy-brain phenotypes, suggesting a shared genetic basis for these traits.
Parasites of the genera Plasmodium and Haemoproteus (Apicomplexa: Haemosporida) are a diverse group of pathogens that infect birds nearly worldwide. Despite their ubiquity, the ecological and evolutionary factors that shape the diversity and distribution of these protozoan parasites among avian communities and geographic regions are poorly understood. Based on a survey throughout the Neotropics of the haemosporidian parasites infecting manakins (Pipridae), a family of Passerine birds endemic to this region, we asked whether host relatedness, ecological similarity and geographic proximity structure parasite turnover between manakin species and local manakin assemblages. We used molecular methods to screen 1343 individuals of 30 manakin species for the presence of parasites. We found no significant correlations between manakin parasite lineage turnover and both manakin species turnover and geographic distance. Climate differences, species turnover in the larger bird community and parasite lineage turnover in non-manakin hosts did not correlate with manakin parasite lineage turnover. We also found no evidence that manakin parasite lineage turnover among host species correlates with range overlap and genetic divergence among hosts. Our analyses indicate that host switching (turnover among host species) and dispersal (turnover among locations) of haemosporidian parasites in manakins are not constrained at this scale.
The attitudes of physicians and drug manufacturers in the US toward patenting pharmaceuticals changed dramatically from the mid-nineteenth century to the mid-twentieth. Formerly, physicians and reputable manufacturers argued that pharmaceutical patents prioritized profit over the advancement of medical science. Reputable manufactures refused to patent their goods and most physicians shunned patented products. However, moving into the early twentieth century, physicians and drug manufacturers grew increasingly comfortable with the idea of pharmaceutical patents. In 1912, for example, the American Medical Association dropped the prohibition on physicians holding medical patents. Shifts in wider patenting cultures therefore transformed the ethical sensibilities of physicians.
IAU Commission 40 for Radio Astronomy (hereafter C40) brought together scientists and engineers who carry out observational and theoretical research in radio astronomy and who develop and operate the ground and space-based radio astronomy facilities and instrumentation. As of June 2015, the Commission had approximately 1,100 members from 49 countries, corresponding to nearly 10 per cent of the total IAU membership.
This article examines the origins of state-level regulations controlling the practice of pharmacy and the manufacture and consumption of dangerous drugs in the Gilded Age. The passage of laws regulating the market in pharmaceuticals grew out of both the precarious economic position of practicing pharmacists and widespread concern for the suffering of individual consumers. As a result, pharmacy laws and other regulations controlling the buying, selling, and use of dangerous drugs during this period should be understood as part of the effort by pharmacists to establish a professional identity for themselves. At the same time, these laws should also be understood as part of the process through which reformers sought to rationalize society toward the goal of protecting the individual consumer. Ironically, however, such efforts were intertwined with the bifurcation of consumer culture into legitimate and illegitimate realms, and with it the creation of the economic and social conditions in which new stories of individual suffering took place.
This study examined whether attachment theory could be used to shed
light on the often high degree of discordance between self- and observer
ratings of behavioral functioning and symptomatology. Interview-based
assessments of attachment organization, using the Adult Attachment
Interview, were examined as predictors of the lack of agreement between
self- and other reports of behavioral and emotional problems among 176
moderately at-risk adolescents. Lack of agreement was measured in terms of
concordance of adolescent and parent or close friend report on equivalent
measures of behavioral and emotional adjustment. Insecure–dismissing
attachment was linked to less agreement in absolute terms between self-
and mother reports of externalizing symptoms, and between adolescent and
close friend reports of behavioral conduct. Insecure–preoccupied
attachment was associated with higher levels of adolescent reporting of
internalizing and externalizing symptoms relative to parent reports of
adolescent symptomatology. The findings suggest that attachment
organization may be one factor that accounts for individual differences in
the degree of discordance between self- and other reports of symptoms in
The goal of this chapter is to explore possible models by which caldesmon and calponin may alter the force-producing interaction between myosin and actin and how the inhibitory activity of caldesmon and calponin may be controlled. Contraction may be potentially regulated by altering the properties of either myosin or actin. In both cases, one or more of many possible transitions in the cycle of ATP hydrolysis by actomyosin may be affected, including (but not limited to) the binding of myosin to actin, the binding of ATP, Pi, and ADP to actomyosin, and cooperative transitions between the active and inactive forms of the actintropomyosin filament. A detailed account of these transitions is not possible here but may be found elsewhere (Chalovich 1992).
Evidence for actin filament-mediated regulation
Phosphorylation of the 20-kDa myosin light chain (MLC20) by the Ca2+ − and calmodulin-dependent myosin light chain kinase (MLCK) is generally thought to be the primary event initiating smooth muscle contraction (for reviews see Kamm and Stull 1985; Somlyo and Somlyo 1994; and Chapter 6 of this volume). In fact, there is evidence that MLC20 phosphorylation is sufficient to trigger smooth muscle contraction (Itoh et al. 1989). On the other hand, numerous physiological studies have shown that there is no fixed relationship between isometric force and MLC20 phosphorylation. During prolonged contraction MLC20 phosphorylation, crossbridge cycling rates, and intracellular Ca2+ decrease while force is fully maintained by the so-called latch state (Dillon et al. 1981; see also Kamm and Stull 1985 for a review).
Political science is a basic discipline in the social sciences. Although it must necessarily maintain close scholarly association with the disciplines of history, economics, sociology, anthropology, geography, and social psychology, political science cannot be considered a part of any of these other social sciences. Political science has its own area of human experience to analyze, its own body of descriptive and factual data to gather, its own conceptual schemes to formulate and test for truth.
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